title: Mitochondrial nitrite reduction coupled to soluble guanylate cyclase activation: lack of evidence for a role in the bioactivation of nitroglycerin.
abstract: Reduction of nitrite to nitric oxide (NO) by components of the mitochondrial respiratory chain may link nitroglycerin biotransformation by mitochondrial aldehyde dehydrogenase (ALDH2) to activation of soluble guanylate cyclase (sGC). We used purified sGC as detector for NO-like bioactivity generated from nitrite and GTN by isolated heart and liver mitochondria. Exogenous NADH caused a pronounced increase in oxygen consumption that was completely inhibited by myxothiazol and cyanide. Oxygen depletion of cardiac mitochondria by NADH was accompanied by activation of sGC and cyanide-sensitive formation of NO. Mitochondrial biotransformation of nitroglycerin was sensitive to ALDH2 inhibitors and coupled to sGC activation but not affected by respiratory substrates or inhibitors. Our data suggest that cytochrome c oxidase catalyzes reduction of nitrite to NO at low O(2) tension but argue against the involvement of this pathway in mitochondrial bioactivation of nitroglycerin.
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kollau
authors.forename: Matteo
authors.initials: M
authors.lastname: Beretta
authors.forename: Michael
authors.initials: M
authors.lastname: Russwurm
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.forename: Wing Ming
authors.initials: WM
authors.lastname: Keung
authors.forename: Kurt
authors.initials: K
authors.lastname: Schmidt
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002417:Cattle; D003486:Cyanides / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D008689:Methacrylates / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D005996:Nitroglycerin / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D003486:Cyanides; D008689:Methacrylates; D009573:Nitrites; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D009243:NAD; D009569:Nitric Oxide; C030517:myxothiazol; D000444:Aldehyde Dehydrogenase; D003576:Electron Transport Complex IV; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin; D010100:Oxygen